Sublingual and buccal medications are administered by placing them in the mouth, either under the tongue (sublingual) or between the gum and the cheek (buccal). The medications dissolve rapidly and are absorbed through the mucous membranes of the mouth, where they enter into the bloodstream. Within the oral mucosal cavity, the buccal, including sublingual, region offers an attractive route of administration for systemic drug delivery. The mucosa has a rich blood supply and it is relatively permeable.
Amongst the various routes of drug delivery, oral route is perhaps the most preferred to the patient and the clinician alike. However, per-oral administration of drugs has disadvantages such as hepatic first pass metabolism and enzymatic degradation within the gastro-intestinal tract, that prohibit oral administration of certain classes of drugs especially peptides and proteins.
Medical gases are pharmaceutical molecules which offer solutions to a wide array of medical needs. More specifically however, gases such as argon, helium, hydrogen, hydrogen sulfide, oxygen, ozone, xenon have recently come under increased exploration in the literature for their potential therapeutic uses in drug withdrawal suppressing effects and with various brain disease states including hypoxia-ischemia, cerebral hemorrhages, and traumatic brain injuries.
Volatile anesthetics have been extensively studied for decades with regard to their potential neuroprotective properties. A colorless, heavy, odorless noble gas, xenon has been of particular interest to researchers because of its possible neuroprotective properties. For example, Petzel and Kox (U.S. Pat. No. 8,143,317) describe the use of xenon for treating neurointoxications. Abraini et al. describe an inhalable gaseous medicament for treating neurointoxications (US2014120184) and for treating ischemic insults (WO2010035074). Still an inhalable aerosol medicament for the treatment or prevention of pain is described in US2002033174.
Argon is recognized to have a significant stabilizing effect on naloxone binding (also naltrexone). Inactivation of naloxone binding to rat brain membrane-bound mu-opioid receptors (Belokonova et al., Biokhimilia. 1993. 58 (12) 1945-1958).
Molecule related to mu-opioid receptors, such as argon, provides benefits to hyperactivity, attention deficit and autism (Rauhut et al., Pharmacol. Biochem Behav. 2002, 73: 611-622; and Aman M G and Langworthy. J. Autism Dev. Disord. 2000. 30: 451-459); sleep disorders (Vasquez-Palacios, 2004); eating and metabolic disorders (King et al., Biol. Psychiatry. 2013, 73: 924-930; and Kurbanov et al., J. Psychopharmacol. 2012, 26: 1244-1251).
Inert gas narcosis, such as argon, induces a decrease of the dopamine release at the striatum level, structure involved in the regulation of the extrapyramidal motricity (Balon et al., Life Sci. 72: 24, 2731-2740, 2003).
Results from in vitro and various animal models have consistently demonstrated organo-protective properties of xenon, mainly in settings of ischemia and reperfusion injury (Derwall et al., Minerva Anestesiol. 75. 37-45, 2009).
Nakao et al. (J Clin Biochem Nutr. January 2009; 44(1): 1-13.) provide an overview of some medicinal therapeutic gas and their use in treating various diseases (see Table 1).
Therapeutic gases have also been used for the treatment of ischemia and reperfusion (Holger K Eltzschig & Tobias Eckle, Nature Medicine 17, 1391-1401 (2011)).
It is clear from the literature that more gases are now being found new uses in therapies.
To date, to carry on these therapies, the volatile anesthetics or gases are administered through the airways by inhalation by the mouth and/or nose, using a mask connected by a gas bottle. Such therapies can currently only be administered at the hospital or in a clinic under supervision for greater control of the administration of the gases through the mask. Moreover, patients are generally not equipped to store gas bottles. Hence, a patient undergoing such gas therapy would need to go to a clinic or to the hospital for receiving the treatment.
Recently, some authors have suggested dissolving gases in water for ingestion as an alternate way to introduce gas in the system (Schoenfeld, 2012).
Further, Britton et al. have developed a pressurization-freeze method to encapsulate Xenon into echogenic liposomes (Xe-ELIP) and have modulated local gas release with transvascular ultrasound exposure (Britton, 2010).
Numerous patents such as U.S. Pat. No. 3,012,893 of Kremzner and Mitchell; U.S. Pat. Nos. 3,985,909 and 3,985,910 of Kirkpatrick and U.S. Pat. No. 4,001,457 of Hegadorn which are incorporated herein by reference, describe gasified candy containing a gas, such as carbon dioxide.
CO2 has also been incorporated in candy or popping candy as apparent from Ahn and Lee (U.S. Pat. No. 5,439,698), Escola Gallart (U.S. Pat. No. 4,952,417) and Bayes Turull (U.S. Pat. No. 5,165,951).
Zeller et al. (U.S. Pat. No. 8,110,241) also describe a foaming soluble coffee powder containing pressurized gas for producing foam at the surface of the beverage.
Darbyshire et al. (U.S. Pat. No. 6,953,592), when faced with the problem of increasing the solubility of powders, have suggested a method of increasing the solubility or dispersibility of such powder using a gas.
Simonsen and Bach (US 20020081738) describe particles comprising a coating and a core particle comprising an active compound, such as an enzyme, wherein the coating comprises a gas component to reduce dust upon making such particles, for the safety of the workers, and to improve elasticity of the particles.
Despite the above, gases used in therapies are still now a day administered by inhalation, and still require the patient to get to a clinic or an hospital for receiving the treatment.
It would be highly desirable to be provided with a new delivery dose vehicle that would allow the patient to uptake its therapeutic gases much like any other compounds formulated in dose caplets or tablets.